JPH03176425A - Fat emulsion - Google Patents

Abstract

PURPOSE:To provide a fat emulsion containing a non-steroidal antiinflammatory analgesic substance, a simple lipid, a phospholipid and water, enabling the selective transfer of a drug into the focus in high efficiency without lowering the pharmacological action of the drug and capable of keeping the blood concentration of the drug. CONSTITUTION:The objective fat emulsion has an average particle diameter of <200nm and contains (A) an active amount of a non-steroidal antiinflammatory analgesic substance, e.g. indomethacin, aspirin or ibuprofen, especially preferably their fat-soluble derivatives, (B) 0.5-30%(W/V) (based on the whole composition) of a simple lipid (e.g. neutral lipid such as refined soybean oil, corn oil and triolein) and sterol derivative such as cholesteryl oleate, (C) 0.15-2 pts.wt. (based on 1 pt.wt. of the component B) of a phospholipid and (D) a proper amount of water. The non-specific incorporation by an endothelial cell system can be avoided to enable the reduction of the necessary dose of the drug.

Description

[Detailed description of the invention] [Industrial application field]

The present invention relates to improved formulations of non-steroidal compounds with anti-inflammatory and analgesic activity. More specifically, at least one non-steroidal anti-inflammatory and analgesic substance, a simple lipid,
The present invention relates to an improved fat emulsion containing phospholipids and water.

[Conventional technology]

Various non-steroidal anti-inflammatory analgesics have excellent anti-inflammatory analgesic effects and are widely used clinically. A variety of studies have been conducted to date on pharmaceutical innovations to improve the migration of drugs from the bloodstream or application site to diseased tissue. For example, a method is known in which drugs are incorporated into liposomes prepared with phospholipids (rDrug Carriersin Biolog
y and Medicine” (1979), B
d.By G. Gregoriadis, Academic Pre
ss). However, with this method, 1) liposomes containing an aqueous layer with a lipid bilayer have many problems with stability during storage, and 2) when administered into the blood, most of the It has the disadvantage that it is taken up into tissues with developed reticuloendothelial system (RES) and is difficult to be distributed to other cells and tissues. This is thought to be because liposomes have a structure in which the inner and outer water layers are separated by a phospholipid bilayer membrane, which makes them unstable against various forces. It was known as a flaw at the time. According to recent research, various drugs have been added to a fat emulsion with a particle size of 0.2 to 0.4 μm consisting of soybean oil and a small amount of egg yolk lecithin, which has been clinically used for nutritional supplementation as a high-calorie infusion. There is a technique for dissolving and using the
806-1813 (1980)). This material has the characteristic that it does not have an internal water layer and can be stored extremely stably compared to liposomes. Particle size 0.2 consisting of this soybean oil and a small amount of egg yolk lecithin
The technology of dissolving various drugs in ~0.4 μm fat emulsions has been applied to various nonsteroidal anti-inflammatory drugs and their fat-soluble derivatives (esterified compounds such as methyl, ethyl, and other higher fatty acids). (Unexamined Japanese Patent Publication No. 58-5991
Publication No. 2, JP-A-58-201712, JP-A-5
9-13720, JP 6144809)
. However, these substances have the property of being quickly taken up non-specifically into the reticuloendothelial system of the liver and the like mentioned above. Although rapid metabolism is desirable for high-calorie infusions, most of the administered drug is transferred to the aum endothelial tissue and other tissues (inflammatory However, this method is not necessarily desirable, and improvements have been desired.

[Problem to be solved by the invention]

Usually, an administered drug moves and distributes within a living body due to the unique properties of the drug molecule. The drug then reaches the site of action and exerts its medicinal effect. At this time, it is preferable that the drug is concentrated only in the areas necessary for the expression of drug efficacy, but in general, the drug is distributed throughout the body, and the drug also moves to areas where it is not needed. This sometimes causes side effects. Therefore, the importance and necessity of improving the pharmacokinetics of drugs arises. In view of the above-mentioned circumstances, the present inventors have devised the following: 1) to enable efficient selective transfer of the drug into the focal tissue without affecting the pharmacological action of the drug itself; Investigate new dosage forms of safer and more effective non-steroidal anti-inflammatory analgesic agents that can reduce the uptake of the drug, ■ maintain blood levels of the drug, and ■ reduce the required drug dosage. As a result of continued efforts, we finally succeeded in completing the present invention.

[Means to solve the problem]

The gist of the present invention is to limit the composition ratios of simple lipids, phospholipids, and water when producing a fat emulsion containing a non-steroidal anti-inflammatory and analgesic substance as a main component. In the present invention, the non-steroidal anti-inflammatory analgesic substance is contained in a determined composition ratio that takes into account its effective amount. In the present invention, simple lipids are contained in an amount of 0.5 to 30% (W/V) based on the entire fat emulsion. In the present invention, the phospholipid is contained in an amount of 0.15 to 2 times the weight ratio of the above-mentioned simple lipid. Water, which is a component of the present invention, is contained in an appropriate amount. The present invention reveals for the first time that a stable micronized emulsion can be obtained with these component compositions, and that this is a fat emulsion with extremely excellent characteristics and can be used as a formulation of a new non-steroidal anti-inflammatory and analgesic substance. became. The fat emulsion of the present invention has the form of an extremely stable fat emulsion. Its average particle size is less than 200 nm. The fat emulsion of the present invention does not contain emulsion grains larger than 1 micron. The fat emulsion of the present invention is an extremely fine and stable fat emulsion. When the average particle diameter is 5 nm or more and less than 200 nm, the particles can easily leak from the inside of the blood vessel into the focal tissue at a site where vascular permeability is increased due to an inflammatory reaction. Blood vessels have various pare systems.
s. Small bore systems up to 9 nm diameter and diameters 25-70
It is said that a large bore system exists, and it is known that the permeability increases further at the lesion site. ) and other intercellular spaces exist, and it is known that vascular permeability is increased in inflammation areas, and in such areas, more of the fat emulsion of the present invention than in blood vessels exists. It leaks selectively and migrates into the diseased tissue. At the same time, the non-steroidal anti-inflammatory and analgesic substance contained in the fat emulsion of the present invention also migrates into the lesion. Due to this,
Since the non-steroidal anti-inflammatory analgesic substance is easily, efficiently and selectively transferred to the lesion site, the concentration of the drug at the lesion site can be increased and its effect can be increased. When the average particle diameter is 1100n or less, 042μrn-0
, the blood concentration of the drug can be maintained significantly higher than that of conventional fat emulsions, which have a diameter of about 4 μm. This is because non-specific uptake of emulsion particles by the reticuloendothelial system is avoided and more emulsion particles are retained in the blood. This results in a significant improvement in the transfer efficiency of the emulsion grains to the lesion site. At the same time, the effect of improving drug-induced liver damage and the like can also be obtained. In the fat emulsion of the present invention, the core of the fat emulsion (for example, soybean oil) is covered and stabilized, compared to the conventional technology which uses a high-calorie infusion consisting of soybean oil and egg yolk lecithin. By using a large amount of the surface layer (for example, egg yolk lecithin) that has the role of In order to form ultrafine particles in the fat emulsion of the present invention, it is necessary that the content ratio of the surface layer (for example, phospholipids) is 0.15 to 2 times the weight ratio of simple lipids. This is because ultrafine particle size increases the surface area of the core of the fat emulsion particle, and it becomes necessary to increase the amount of phospholipid in order to cover and stabilize the core as a surface layer. If a smaller amount of phospholipid is used, it is impossible to obtain a stable fat emulsion with an average particle diameter of 200 nm, and the contamination of coarse particles is unavoidable. If a larger amount of phospholipid is used, contamination with liposome particles is unavoidable. The content of the non-steroidal anti-inflammatory analgesic substance in the fat emulsion of the present invention can be varied depending on the pharmacological activity of each non-steroidal anti-inflammatory analgesic substance. In either case, an effective amount of drug can be contained. However, it is generally desirable to set it to 5% (W/V) or less. According to the present invention, since the non-steroidal anti-inflammatory analgesic substance is present in lipid oil droplets, it exists in a state where it is isolated from the surrounding environment, and therefore enzymatic or non-enzymatic decomposition can be suppressed. , the stability of the drug can be improved even after administration. It was revealed for the first time by the present invention that a stable ultrafine-grained fat emulsion can be obtained with this component structure, and that this can be used as an extremely excellent fat emulsion. The non-steroidal anti-inflammatory analgesic substance according to the present invention includes compounds that have been conventionally used in conventional fat emulsions having a particle size of about 0.2 μm to 0.4 μm,
Fat-soluble nonsteroidal anti-inflammatory analgesic substances and fat-soluble derivatives can be applied as they are. For example, indomethacin, flurbiprofen, 4-biphenylylacetic acid compound, aspirin, salicylic acid, methyl salicylate, ibuprofen, flufenamic acid, ketoprofen, and their methyl, ethyl, isopropyl, butyl, geranyl, fufurnesyl-valmitic acid,
At least one selected from the group of various fat-soluble derivatives such as heptyl, tocopherol, glycerol, and cholesterol, all of which are stably retained in the emulsion grains of the present invention, but generally the above-mentioned Fat-soluble derivatives are preferred. This is because derivatization increases the lipid solubility of the drug, making it easier to retain a large amount of the drug in the emulsion particles. Examples of the simple lipid according to the present invention include purified soybean oil,
Neutral lipids such as cottonseed oil, rapeseed oil, sesame oil, corn oil, peanut oil, safflower oil, triolein, triolein, tripalmitin, tristearin, trimyristin, and triarachidonin can be mentioned. Further examples include sterol derivatives such as cholesteryl oleate, cholesteryl oleate, cholesteryl myristate, cholesteryl palmitate, and cholesteryl arachidate. Neutral lipids are relatively easily degraded by various lipases present in vascular endothelium, etc., whereas
It is preferable as a component of the present invention because it is less susceptible to L-katsudojiru 2 sun - phantom - 2 small harm ■ - upper 4 mackerel, and its stability in the body is further increased. Examples of the phospholipid according to the present invention include egg yolk, soybean,
Examples include phospholipids derived from cows, pigs, etc., and phospholipids obtained purely synthetically or semi-synthetically. That is, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol,
Such as phosphatidylglycerol. Also, for example,
Examples include egg yolk phosphatidylcholine, soybean phosphatidylcholine, dipalmitoylphosphatidylcholine, simyristoylphosphatidylcholine, distearoylphosphatidylcholine, dioleoylphosphatidylcholine, dipalmitoylphosphatidylglycerol, and the like. These hydrogenated substances can also be used. Among them, purified egg yolk lecithin can be mentioned as a representative example. Furthermore, charged lipids such as stearylamine, dicetyl phosphate, phosphatidic acid, and phosphatidylglycerol can also be used to impart a surface charge to the emulsion grains. In producing the fat emulsion of the present invention, various conventional emulsion production methods can be applied as they are. For example, a common method is to sufficiently micronize all components including the drug using a pressurized jet homogenizer such as a Manton-Gallalin type homogenizer, a microfluidizer, an ultrasonic homogenizer, or the like. At this time, physiologically acceptable sterols, fatty acids, derivatives thereof, etc. can also be added as generally known emulsification aids or stabilizers. Typical examples of these include cholesterol, oleic acid, and the like. The shape and particle size of the fat emulsion of the present invention can be easily confirmed using an electron microscope, a light scattering particle size analyzer, filtration using a membrane filter, or the like. In addition to the main component of the present invention, the fat emulsion of the present invention may contain, for example, additives and auxiliary substances commonly used in injections. Suitable examples of these include antioxidants, preservatives, stabilizers, tonicity agents, buffers, and the like. The required amount and optimum amount of these additives, auxiliary substances, etc. can be changed depending on the purpose. The fat emulsion of the present invention obtained as described above can be sterilized (for example, filter sterilization, high-pressure steam sterilization, etc.) as necessary, and sealed in an ampoule together with nitrogen gas. It can also be freeze-dried if necessary. The lyophilized fat emulsion of the invention can be reconstituted by addition of a suitable solution. The preparation comprising the fat emulsion of the present invention can be administered intravenously to humans or various animals for the purpose of treating or preventing various inflammations such as rheumatism, and for analgesic effects after surgery or during various diseases. Common. In this case, the grain size of the emulsion grains, etc. should be sufficiently controlled.
This is because it is known that various types of toxicity occur when particles of +n4t are mixed in. Furthermore, the preparation comprising the fat emulsion of the present invention can be administered as an injection intraarterially, intramuscularly, intrathecally, subcutaneously, etc., as with conventional products, if necessary. Furthermore, the fat emulsion of the present invention can be formulated and used as eye drops, nasal drops, oral preparations, inhalants, bladder injections, heavy doses, ointments, and the like. Even in this case, the fat emulsion of the present invention may contain pharmaceutically acceptable additives such as bases and excipients in addition to the main components of the present invention. The dosage of the formulation comprising the fat emulsion of the present invention varies depending on the administration route, dosage form, symptoms, and purpose, but is generally 1 to 10,100 O/dose as an emulsion.

【effect】

According to the present invention, the clinical utility value of non-steroidal anti-inflammatory and analgesic substances can be significantly increased. The effects of the present invention are that it overcomes the conventional problems and that it does not adversely affect the pharmacological action of the drug itself. f
It enables selective indulgence in phlegm, ■ maintains the blood concentration of the drug, ■ reduces the required drug dosage, and ■ does not use harmful additives. This can be summarized as the achievement of a new formulation of a safer and more effective non-steroidal anti-inflammatory analgesic substance. These effects were achieved for the first time by the present invention. Since the constituent components of the fat emulsion of the present invention are mainly medically acceptable lipids that have been conventionally used for medical purposes in medical settings, they can be used extremely safely. This is also one of the important effects of the present invention.

【Example】

The present invention will be described in more detail below with reference to Examples relating to the production of fat emulsions of the present invention, but it is clear that the present invention is not limited to these examples. Production Example 1 After heating and mixing 0.181 palmitic acid ester of methyl salicylate, 2.5 g of purified soybean oil, and 1.5 g of purified egg yolk lecithin at 40 to 70°C, 50 ml of 0.24 M aqueous glycerin solution was added to the mixture. Add and stir with a homogenizer to make a rough emulsion. The mixture was emulsified for 66 minutes using an ultrasonic homogenizer (Planson Model 185) under water cooling to obtain an extremely fine fat emulsion. Production Example 2 1 g of flurbiprofen, 50 g of purified soybean oil, and 50 g of purified egg yolk lecithin were heated and mixed at about 60°C, and to this,
Add 0.24M glycerin aqueous solution (50%) and stir with a homomixer to make a rough emulsion.
High pressure (800 to 120
0 kg/am) to obtain an extremely fine fat emulsion. Production Example 3 0.1 g of ibuprofen, 2 g of purified soybean oil, and 3 g of purified egg yolk lecithin were mixed in chloroform/methanol (1/1,
v/v) After mixing and dissolving in a mixed solution 100-, the solvent was completely removed under reduced pressure using a rotary evaporator. Add 8rnp of isotonic phosphate buffer to this and stir with a homogenizer to obtain a rough emulsion. Add isotonic phosphate buffer for 50 min.
- and then emulsified for 60 minutes with an ultrasonic homogenizer (Branson Model 185) under water cooling to obtain an extremely fine fat emulsion. Production Example 4 2 g of indomethacin farnesyl ester, 20 g of fiI soybean oil, and purified egg yolk lecithin. 18g were heated and mixed at about 60℃, and 0.24M glycerin aqueous solution was added to it.
oml and stir with a homomixer to make a rough emulsion. The crude emulsion was high-pressure emulsified using a microfluidizer to obtain an extremely fine fat emulsion. Production Example 5 0.1 g of ibuprofen methyl ester, 0.5 g of cholesteryl oleate, and 0.5 g of purified egg yolk lecithin were added to a mixture of chloroform/methanol (1/1, V/V) 10
After mixing and dissolving in 0ml, the solvent was completely removed under reduced pressure using a rotary evaporator. Add to this 8mj of 0.24M glycerin aqueous solution! Add and stir with a homogenizer to make a rough emulsion. A 0.24M aqueous glycerin solution was added to adjust the volume to 10-1, and the mixture was emulsified for 60 minutes using an ultrasonic homogenizer (Planson Model 185) to obtain an extremely fine fat emulsion. Production example 6 4-biphenylylacetic acid ethyl ester 50 mg, fi
0.5g of soybean oil manufactured by T, and 0.4g of purified egg yolk lecithin,
Similis, toyl phosphatidylglycerol 0.1g
chloroform/methanol (1/Lv/v) mixture 10
After mixing and dissolving in 0ml, the solvent was completely removed under reduced pressure using a rotary evaporator. Add 8 ml of 9% lactose aqueous solution to this and stir with a homogenizer to obtain a rough emulsion. Add 9% lactose aqueous solution and make 10ml! After adjusting the volume to 1, the mixture was emulsified for 60 minutes using an ultrasonic homogenizer (Planson Model 185) to obtain an extremely fine fat emulsion. Production example Fibuprofen geranyl ester 50 ■ Refined soybean oil 0
．． 5 g, and 0.4 g of hydrogenated egg yolk lecithin. 0.1g of cholesterol in chloroform/methanol (
l/1, v/v) mixed liquid 100mf! After mixing and dissolving in a rotary evaporator, the solvent is completely removed under reduced pressure. Add 9% lactose aqueous solution 3rd to this and stir with a homogenizer to obtain a rough emulsion. Add 9% lactose aqueous solution and make 10ml! After adjusting the volume to 1, the mixture was emulsified for 60 minutes using an ultrasonic homogenizer (Planson model 185) to obtain an extremely fine fat emulsion. Production Example 8 Acetylsalicylic acid cholesteryl ester 50 mg. 0.5 g of purified soybean oil and 0.4 g of purified egg yolk lecithin were mixed in chloroform/methanol (1/1, v/v) 10
After mixing and dissolving in 0ml, the solvent was completely removed under reduced pressure using a rotary evaporator. Add 8 rnl of 9% lactose aqueous solution to this and stir with a homogenizer to obtain a rough emulsion. After adding 9% lactose aqueous solution and adjusting the volume to 10-1, use an ultrasonic homogenizer (Planson model 1
85) for 60 minutes to obtain an extremely fine fat emulsion. Production Example 9 0.1 g of glyceryl tribiphenylacetate. 0.5 g of cholesteryl oleate and 0.5 g of purified egg yolk lecithin were mixed in chloroform/methanol (1/1, v/
v) After mixing and dissolving in a 100% mixed solution, completely remove the solvent under reduced pressure using a rotary evaporator. To this, 0
．． Add 8 rnl of 24 M glycerin aqueous solution and stir with a homogenizer to obtain a rough emulsion. After adding 0.24M glycerin aqueous solution and adjusting the volume to 10mf, use an ultrasonic homogenizer (Planson model 18
5) was emulsified for 60 minutes to obtain an extremely fine fat emulsion. Production Example 10 0.5 g of albumin was added to the non-steroidal anti-inflammatory and analgesic substance-containing fat emulsion obtained in Production Examples 1.5 and 6, followed by freeze-drying to obtain a dry preparation. Measurement of Particle Size The particle size of the fat emulsions of Production Examples 2 and 5 was evaluated using a dynamic light scattering particle size measuring device using laser light. As a result, the particle diameter was about 15 to about 150 nm. Further, it did not contain particles larger than lμ. It is clear that the fat emulsion of the present invention consists of extremely fine and uniform emulsion grains. Furthermore, when administered intravenously, it is clear that effective and safe drug therapy can be achieved because it does not contain particles larger than 1 μm, which would pose a toxicity problem.

Claims (1)

[Claims] (1) (a) an effective amount of a non-steroidal anti-inflammatory analgesic substance, (b) 0.5-30% (w/v) of the total simple lipid;
(c) phospholipids in an amount of 0.15 to 2 times (weight ratio) relative to simple lipids, and (d) an appropriate amount of water in the above (a), (b), (c), and (d). A fat emulsion or a freeze-dried preparation thereof.